The Mitogen Activated Protein (MAP) Kinase has been implicated in the regulation of several essential cellular processes such as proliferation, differentiation and apoptosis. The regulation of this important pathway has been the focus of many studies. In PC12 cells the sustained activation of MAPK leads to differentiation while the transient activation leads to proliferation. It remains unclear the mechanism underlying the difference in magnitude of activation of MAPK 1,2 but it has been hypothesized that it involves regulatory contributions from the cAMP signaling cascade. Here we present a novel regulatory feedback loop that may be able to promote the sustained activation of MAPK 1,2 in response to growth factors. This loop involves the differential expression of the cyclic nucleotide phosphodiesterase PDE4D long and short isoforms. Depending on the predominant ratios of long to short PDE4D isoforms found in PC12 cells, the activation of MAPK can be sustained or transient. We propose the use of novel computational modeling techniques along with experimental data to characterize this regulatory loop and understand its significance in the regulation of the cellular fate of PC12 cells.